1. Field of the Invention
The present invention relates to isoquinoline compounds that may affect the action of G protein-coupled receptor kinases in a cell and that are useful as therapeutic agents or with therapeutic agents. In particular, these compounds are useful in the treatment of eye diseases or ocular disorders such as glaucoma.
2. Background
A variety of hormones, neurotransmitters and biologically active substances control, regulate or adjust the functions of living bodies via specific receptors located in cell membranes. Many of these receptors mediate the transmission of intracellular signals by activating guanine nucleotide-binding proteins (G proteins) to which the receptor is coupled. Such receptors are generically referred to as G-protein coupled receptors (GPCRs) and include, among others, α-adrenergic receptors, β-adrenergic receptors, opioid receptors, cannabinoid receptors and prostaglandin receptors.
The G-protein coupled receptors play an important role in the regulation of various physiological functions. By way of example, GPCRs have been implicated in a number of disease states, including, but not limited to: cardiac indications such as angina pectoris, essential hypertension, myocardial infarction, supraventricular and ventricular arrhythmias, congestive heart failure, atherosclerosis, renal failure, diabetes, respiratory indications such as asthma, chronic bronchitis, bronchospasm, emphysema, airway obstruction, upper respiratory indications such as rhinitis, seasonal allergies, inflammatory disease, inflammation in response to injury, rheumatoid arthritis, chronic inflammatory bowel disease, glaucoma, hypergastrinemia, gastrointestinal indications such as acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastrointestinal reflux, peptic ulcer, Zollinger-Ellison syndrome, pain, obesity, bulimia nervosa, depression, obsessive-compulsive disorder, organ malformations (for example, cardiac malformations), neurodegenerative diseases such as Parkinson's Disease and Alzheimer's Disease, multiple sclerosis, Epstein-Barr infection and cancer.
The balance between the initiation and the turn off of the intracellular signal, called desensitization, regulates the intensity and duration of the response of the receptors to stimuli such as agonists. Desensitization of agonist-occupied GPCRs results from their phosphorylation by specific kinases called G protein-coupled receptor kinases (GRKs) and the subsequent binding of arrestin proteins to phosphorylated receptors. Arrestins are a family of intracellular proteins that bind activated GPCRs, including those that have been agonist-activated, and especially those that have been phosphorylated by G protein-coupled receptor kinases. The binding of the arrestins prevents further stimulation of G proteins and downstream signaling pathways. When desensitization occurs, the mediation or regulation of the physiological function mediated or regulated by the G proteins to which the receptors are coupled is reduced or prevented. For example, when agonists are administered to treat a disease or condition by activation of certain receptors, the receptors become desensitized from the action of the GRKs such that agonist administration may no longer result in therapeutic activation of the appropriate receptors. At that point, administration of the agonist no longer enables sufficient or effective control of or influence on the disease or condition intended to be treated.
In view of the role of GRKs in the desensitization of GPCRs, there is a need in the art for agents that prevent or reduce the desensitization of the GPCRs by controlling or inhibiting the action of the corresponding GRKs.